4-(P-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases

Abstract

Methods of treating or suppressing mitochondrial diseases, such as Friedreich's ataxia (FRDA), Leber's Hereditary Optic Neuropathy (LHON), mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS), Kearns-Sayre Syndrome (KSS), are disclosed, as well as compounds useful in the methods of the invention, such as 4-(p-quinoly)-2-hydroxybutanamide derivatives. Methods and compounds useful in treating other disorders such as amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease, and pervasive developmental disorders such as autism are also disclosed. Energy biomarkers useful in assessing the metabolic state of a subject and the efficacy of treatment are also disclosed. Methods of modulating, normalizing, or enhancing energy biomarkers, as well as compounds useful for such methods, are also disclosed.

What is claimed is: 
     
       1. A compound of Formula A: 
       
         
           
           
               
               
           
         
         wherein: 
         R 5  is hydrogen, and R 6  is C 1 -C 6 -alkyl; where the alkyl group is optionally substituted with —S(O) 0-2 R 10 , —CN, —F, —Cl, —Br, —I, —NR 10 R 10 , C 3 -C 6 -cycloalkyl, aryl, heteroaryl, heterocyclyl, —C(O)—R 11 , —C(O)—C 0 -C 6 -alkyl-aryl, —C(O)—O—R 11 , —C(O)—O—C 0 -C 6 -alkyl-aryl, —C(O)—NR 11 R 11 , —C(O)—NH—C 0 -C 6 -alkyl-aryl, —NH—C(O)—R 11 , or —NH—C(O)—C 0 -C 6 -alkyl-aryl; where the aryl, heteroaryl, and heterocyclyl ring substituents are optionally further substituted with halo, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, oxo, hydroxy, C 1 -C 6 -alkoxy, —C(O)—C 1 -C 6 -alkyl, or —C(O)—O—C 1 -C 6 -alkyl; 
         and where one of the carbons of the R 6  C 1 -C 6 -alkyl group is replaced with a heteroatom selected from the group consisting of —O—, —N—, and —S—; 
         and wherein the R 6  C 1 -C 6 -alkyl group is cyclic or a combination of cyclic and linear or branched; 
         R 10  and R 10′  are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, aryl, aryl-C 1 -C 6 -alkyl, heteroaryl, heterocyclyl, —C(O)—H, —C(O)—C 1 -C 6 -alkyl, —C(O)-aryl, and —C(O)—C 1 -C 6 -alkyl-aryl; and 
         R 11  is selected from the group consisting of hydrogen and C 1 -C 6 -alkyl; 
         or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 
       
     
     
       2. The compound of  claim 1 , where R 6  is unsubstituted; or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 
     
     
       3. The compound of  claim 1 , where the R 6  C 1 -C 6 -alkyl group is cyclic or a combination of cyclic and linear; or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 
     
     
       4. The compound of  claim 1 , where the R 6  C 1 -C 6 -alkyl group is cyclic; or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 
     
     
       5. The compound of  claim 1 , where one of the carbons of the R 6  C 1 -C 6  alkyl is replaced with —O— or —N—; or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 
     
     
       6. The compound of  claim 1 , where one of the carbons of the R 6  C 1 -C 6 -alkyl is replaced with an —O— or —N— and where the R 6  C 1 -C 6 -alkyl is cyclic or a combination of cyclic and linear; or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 
     
     
       7. The compound of  claim 1 , where one of the carbons of the R 6  C 1 -C 6 -alkyl is replaced with an —O— or —N— and where the R 6  C 1 -C 6 -alkyl is cyclic; or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 
     
     
       8. The compound of  claim 1 , where R 6  is cyclopentylmethyl, cyclopentyl, or cyclohexyl, and where one of the carbons of R 6  is replaced with —O— or —N—; or a salt, a stereoisomer, or a mixture of stereoisomers thereof. 
     
     
       9. The compound of  claim 1 , which is 6-hydroxy-2,5,7,8-tetramethyl-N-((tetrahydrofuran-2-yl)methyl)chroman-2-carboxamide; or a salt, a stereoisomer, or a mixture of stereoisomers thereof.